Method for preparing a material for medical or veterinary use, resulting material, and uses thereof

ABSTRACT

A method for preparing a material for medical or veterinary use by uniformly mixing a thermoplastic polymer, preferably polyether etherketone (PEEK), at least with tricalcium phosphate (Ca 3  (PO 4 ) 2 ), and injection or extrusion moulding the resulting mixture under conditions suitable for converting the tricalcium phosphate into calcium hydroxyapatite. tite. The basic mixture preferably comprises a biocompatible metal oxide such as titanium dioxide (TiO 2 ). The resulting material is useful for making endosseous implants or bone prostheses.

FIELD OF THE INVENTION

This invention relates to a process for obtaining a material for medicalor veterinary uses, designed especially, but not exclusively, for theexecution of endo-osseous implants, notably dental ones, or theexecution of osseous prosthesis. The invention also relates to thematerial obtained by the process as well as its applications.

BACKGROUND OF THE INVENTION

Numerous types of materials, either metallic or plastic, are used in themedical or veterinary field, for the replacement of biologicalstructures (bones especially) or the fixation of functional organs(dental implants or others, . . .).

The selection of the material is made in relation to its structuralintrinsic characteristics and also in relation to its biocompatibility,in terms of integration or, what is better, in terms of biologicaltolerance.

For informative purposes, the document EP-A-0378102 describes animplantation material obtained by extrusion moulding of a thermoplasticpolymer mixture with calcium hydroxyapatite and additional chargingconstitutive elements.

The document US-A-4645503 suggests a bone reparation material comprisinga biocompatible and biodegradable thermoplastic polymer, mouldable atordinary temperature and mixed with a filler, preferably calciumhydroxyapatite, tricalcium phosphate or glass granules, used alone or incombination.

SUMMARY OF THE INVENTION

The purpose of the present invention is to offer a cheap and easy toimplement process, enabling to obtain a material which combines goodgeneral mechanical qualities and excellent biocompatibility in terms ofbiological tolerance, liable to allow particularly efficient usage inthe medical and veterinary fields.

Another purpose of the invention is to offer a process allowing toobtain a material whose constitution is close to that of the bone.

The process complying with the present invention consists in mixinghomogeneously a biocompatible thermoplastic polymer with tricalciumphosphate (Ca₃ (PO₄)₂). The mixture obtained then undergoes an injectionor extrusion type moulding operation, under suited conditions(especially temperature and pressure) to ensure the transformation ofthe tricalcium phosphate into calcium hydroxyapatite (Ca₅ (PO₄)₃ OH).

The transformation during the moulding operation is performed accordingto the following reaction:

    5Ca.sub.3 (PO.sub.4).sub.2 +3H.sub.2 O→3Ca.sub.5 (PO.sub.4).sub.3 OH+H.sub.3 PO.sub.4

The presence of calcium hydroxyapatite allows the moulded material tocome close to the natural composition of the bone in order to enhanceits biocompatibility.

In addition to the calcium hydroxyapatite formed out of the tricalciumphosphate, one can expect to add a small proportion to the basicmixture, before moulding.

The above reaction is carried out partially and the moulded end-productcontains residual tricalcium phosphate. Tricalcium phosphate is one ofthe basic biological compounds for the formation of calciumhydroxyapatite; it also exhibits a healing function and it isresorbable.

Orthophosphoric acid (H₃ PO₄) as such is prescribed as calcium fixativeand as acidifying agent; this therapy is little active; however, itenjoys newly found favours by the use of high doses of alkalinephosphates and of glycerophosphates in affections where the calciummetabolism is disturbed. The orthophosphoric acid is a fundamentalconstitutive element of the nucleotides: a nucleotide is formed of apuric or pyrimidic basis to which has been attached by a glucosidic linka sugar combined to a molecule of phosphoric acid. Nucleotide is thebasis unit of the nucleic acids. Nucleic acids combined to one orseveral protein molecules produce nucleoproteins, which constitute animportant part of the cores of the cells and can also be traced in thecytoplasm. Thus, phosphorus is a fundamental element of living matterand of biochemistry.

Orthophosphoric acid (H₃ PO₄) is derived from the transformation processof tricalcium phosphate into calcium hydroxyapatite; this product isvolatile, but it remains present in the moulded end-material. Possibly,it may be added to the basic mixture, before moulding.

The biocompatible thermoplastic polymer has a linking function; it hasbeen chosen for its physical properties after forming. Forexemplification purposes, one can use a polyether-etherketone, aspolyether-ketone, a polysulfone, a polytetrafluoro-ethylene, apolyether-block-amids or a polyimide.

Due to its YOUNG's modulus and to its interesting structurecharacteristics, close to those of the bone, polyether-etherketone(PEEK) will be used preferably. PEEK is a semi-crystalline polymerformed of an aromatic linear chain based on the repetition of thefollowing units: ##STR1##

The characteristics of this polymer are detailed in the commercialleaflet published in 1992 by the ICI MATERIALS Company "Victrex PEEK,the high temperature engineering thermoplastic--Properties andprocessing."

Moreover, the basic composition, before moulding, may advantageouslycomprise one or several agents liable to foster the formation of calciumhydroxyapatite and/or liable to improve the radio-opacity of the mouldedmixture. One can thus add one or several biocompatible metallic oxides,selected among ceramics such as titanium dioxide (TiO₂), zirconiumdioxide (ZrO₂) or aluminium oxide (Al₂ O₃).

The disinfecting side effect of titanium dioxide can be an importantcriterion of selection.

These metallic oxides can play a catalysing role in the chemicalreaction; they exhibit a high molar mass which will enable to reinforcethe radio-opacity of the thermoplastic.

The material according to the invention is formed by moulding, injectionor extrusion type, of a homogeneous mixture of constitutive elements.The material and the moulding conditions are suited to this mixture andespecially to the basic thermoplastic.

The starting homogeneous mixture contains tricalcium phosphate, acompound capable of being transformed into calcium hydroxyapatite duringthe moulding operation in combination with the kneading action of thewormgear and the temperature and pressure rises; ice may also containcalcium hydroxyapatite in the form of Ca₁₀ (PO₄)₆ OH₂, as well as one orseveral metallic oxides.

In order to keep a mouldable material with the desired behaviour andresistance, the thermoplastic polymer represents at least 65% in weightof the end-material. On the other hand, in order to bring enoughchemical elements designed for fostering biological integration, theadditional components (tricalcium phosphate, calcium hydroxyapatite andmetallic oxide (TiO₂)) will represent between 10 and 35% in weight ofthe end-material.

Obviously, for particular application, the proportions of the materialsimplied may differ.

A good compromise, especially in terms of mechanical properties(hardness, resilience, tensile, deflection and torsion behaviour) willcorrespond to more or less 80% of thermoplastic polymer and 20% ofadditional components.

DETAILED DESCRIPTION OF THE INVENTION EXAMPLES

Basic mixtures are performed out of polyether-etherketone (PEEK),calcium dihydroxyapatite, tricalcium phosphate (Ca₃ (PO₄)₂) and titaniumdioxide (TiO₂).

Another basic mixture is performed out of polyether-etherketone (PEEK),tricalcium phosphate (Ca₃ (PO₄)₂) and titanium dioxide (TiO₂).

PEEK is available in the form of powder or granules (size: approx. 100microns), distributed by the THERTEC SA Company, 78370 PLAISIR-FRANCE;the reference of the PEEK used is "450 G pf", this especially because ofits presentation in terms of granulometry, in order to optimize themixture with the other constitutive elements.

The calcium dihydroxyapatite used is distributed by BIOLAND SARL, 31100TOULOUSE-FRANCE; it is available in the form of a white powder.

The tricalcium phosphate is available in powder form (grains of size inthe order of 200 microns); it is for instance marketed by theCooperation Pharmaceutique Francaise, S.A., 77020 MELUN-FRANCE.

The titanium dioxide is also available in the form of a powderdistributed by the Cooperation Pharmaceutique Francaise, S.A., 77020MELUN-FRANCE.

a) Proportions

The components above are present in the following proportions:

Mixture 1 (10% loads)

PEEK: 90% in weight

Ca3 (PO4)2: 4% in weight

TiO2: 4% in weight

Ca10 (PO4)6 OH2: 2% in weight

Mixture 2 (20% loads)

PEEK: 80% in weight

Ca3 (PO4)2: 9% in weight

TiO2: 9% in weight

Ca10 (PO4)6 OH2: 2% in weight

Mixture 3 (30% loads)

PEEK: 70% in weight

Ca3 (PO4)2: 14% in weight

TiO2: 14% in weight

Ca10 (PO4)6 OH2: 2% in weight

Mixture 4 (35% loads)

PEEK: 65% in weight

Ca3 (PO4)2: 16.5% in weight

TiO2: 16.5% in weight

Ca10 (PO4)6 OH2: 2% in weight

Mixture 5

PEEK: 80% in weight

Ca3 (PO4)2: 10% in weight

TiO2: 10% in weight

b) Kneading

The constitutive elements of each mixture are placed in a turbine mixeruntil perfect homogenization.

c) Drying

Each mixture obtained is dried in an air circulation stove for 3 hoursat 150° C.

d) Moulding

The moulding operation is performed on a KRAUSS-MAFFEI type injectionpress, model 90-340-32, KRAUSS MAFFEI FRANCE, 92632GENNEVILLIERS-FRANCE.

The preparation conditions of the material and the moulding conditionsof the mixture correspond to those used for the pure PEEK, in compliancewith the commercial leaflet "ICI MATERIALS" introduced above.

As the PEEK is a semi-crystalline thermoplastic, it is necessary to heatthe mould, failing which the surface finish of the moulded parts wouldbe negatively affected. Indeed, the surface veil would be in anamorphous phase and the core in a crystalline phase; if the mould weretoo cold, the parts could even taken on a totally amorphous characterand the mechanical characteristics would drop severely.

Thermal control of the mould is ensured by an oil re-heater enabling tomaintain it at a temperature of approx. 160° C. Insulation means limitthermal dispersions and preserve the peripheral organs of the injectionpress. These means can be insulating plates formed of a complex of glassfibre.

For series injections, a vibrator shall be advantageously fixed on thesieve in order to foster the flowing of the mixture.

Generally, the moulding is performed at a temperature comprised between340° and 400° C. and at an injection pressure from 70 to 140 MPa.

The form of the mould can vary in relation to the part that one wishesto obtain, for instance for the execution of an osseous prosthesis,notably for orthopedic applications. One can also obtain a bloc ofmatter that will be then cut or machined according to the shape desired,for osseous filling or an implant, of a dental type for instance.According to the applications foreseen, one could also integrate theexecution of filaments which, after knitting or weaving, will be used asa jacket, protection or support membrane.

Results

a) Mechanical tests

tensile test

These tests have been carried out on a tensile machine INSTRON, Model4302, INSTRON S.A., 78284 GUYANCOURT-FRANCE.

The test pieces used have a cross section of 40 mm and a length betweenjaws of 80 mm, The stress are measured in relation to the deformationpercentages; the results appear on the curves of FIGS. 1 to 5 with thedeformation (%) in abscissae and the stress (MPa) as an ordinate.

FIG. 1 corresponds to a test on pure PEEK;

FIG. 2 corresponds to the test on mixture 1;

FIG. 3 corresponds to the test on mixture 2;

FIG. 4 corresponds to the test on mixture 3 and

FIG. 5 to the test on mixture 4.

From the curves obtained, the tangent modulus of the material can bedetermined which is the original slope of the curve.

The results are shown on the tables hereunder where:

E: tangent modulus

SgM: maximum stress

SgR: breaking stress

SgP: stress beyond the limit of proportionality

A: maximum elongation

    ______________________________________                                            A    E (MPa)     SgM (MPa) SgR (MPa) SgP (MPa)                                            (mm)    ______________________________________    Pure PEEK    Mean   2525     95.7      77.7    38.9    35.09    Standard           66       2.6       3.3     2.35    11.27    deviation    10% mixture    Mean   2577     90.6      70.8    36.7    12.16    Standard           126      1.13      1.13    2.4     0.78    deviation    20% mixture    Mean   2967     90        83      35      5.63    Standard           45       0         6.4     0       0.51    deviation    30% mixture    Mean   3637     76.2              37.5    3    Standard           47.5     2.8               2.5     1    deviation    35% mixture    Mean   3684     75.7              33.3    2.11    Standard           35.3     6.1               2.4     0.19    deviation    ______________________________________

The pure PEEK and the 10% mixture exhibit the behaviour of avisco-elastic thermoplastic with a threshold. The 20% mixture has avisco-elastic behaviour without threshold; the 30 and 35% ones have afragile behaviour.

As a summary, the larger the load, the more the compound resistsdeformation, but the more brittle it is.

resilience test

The resilience tests have been carried out on a pendulum rack impacttesting machine of CEAST make, model 6548, ADAMEL LHOMARGY Company,94203 IVRY SUR SEINE-FRANCE. The method selected is that of the Charpypendulum rack impact testing machine. The purpose is to measure theresistance to shocks in Kj/m .

The resistance to shocks is given by the relation: R = E/S with E =absorbed energy and S = cross section of the test-piece (40 mm ).

After test, the following results are obtained:

    ______________________________________    Load %     0        10      20     30   35    Mean E (J) 30.8     18.36   3.39   2.34 1.61    E (J) standard               4.8      1.35    0.47   0.11 0.15    deviation    R (kJ/m**) 770      459     84.8   58.45                                            40.2    ______________________________________     with mean E: energy absorbed during the shock     R: resistance to the shock in kJ/m**

It appears that the more the load increases in the mixture, the less theformer resists to shocks. This reduction is more progressive from 20 to35% of loads, whereas the value drop drastically from 0 to 20% of loads.

flexural test

The method used is the vibratory flexure with three embedding links andtemperature sweep, called "Dual cantilever". These tests have beencarried out on a visco-elasticimeter Rheometrics, RSA II type,RHEOMETRICS FRANCE, 77436 MARNE LA VALLEE-FRANCE.

The purpose is to determine the flexural modulus E' in relation totemperature. Sweeping enables, among other things, to visualise thevitreous transient temperature beneath which it is necessary to remainduring machining. It is characterised by a drop of the flexural modulus.

The following table exhibits, for a given temperature, the value of theflexural modulus E' for a certain load of the mixture.

    ______________________________________    Load %       Temperature (°C.)                             E' (MPa)    ______________________________________     0           31.79       3300    10           29.48       2781.1    20           31.3        3117.8    30           30.68       3865.2    35           31.31       3717.1    ______________________________________

A drop of the modulus value for the 10% mixture can be noticed, then aconstant progression for the following loads before a slight degradationfor the 35% mixture.

torsional test

A tensile machine INSTRON (model 4302, INSTRON S.A., 78284GUYANCOURT-FRANCE) is used, as well as a mechanical device whichtransforms the tensile movement into rotation. The latter is turned intoa mechanical welding apparatus thanks to a precision assembly. Torquingand angular values are then derived from the force and displacementvalues.

The purpose is to determine the shear modulus G, commonly called themodulus of COULOMB.

The tests are performed on cylindrical pieces, 8 mm in diameter and 40mm in length.

In the result tables below:

G: modulus of elasticity in shear (Coulomb)

Cmax: maximum torque

Cadm: maximum admissible torque

μ: angular/length limit

    ______________________________________    G (MPa)      Cmax (N · m)                             Cadm (N · m)                                        μ (°/mm)    ______________________________________    Pure PEEK    Mean    1190.5   8.13        3.17     2.25    Standard            48.1     0.13        0.23     0.1    deviation    10% mixture    Mean    1185     7.18        3.08     2.34    Standard            57       0.02        0.12     0.14    deviation    20% mixture    Mean    1475     7.52        3.33     2.57    Standard            34.4     0.02        0.12     0.01    deviation    30% mixture    Mean    1763     8.75        2.83     1.9    Standard            58       0.35        0.31     0.3    deviation    35% mixture    Mean    1738     5.26        2.28     0.625    Standard            107.6    1.13        0.33     0.26    deviation    ______________________________________

It can be observed that the heavier the load, the more resistant thesample to the torsional stresses. However, the shear modulus at 10% isnot higher than that of the pure PEEK, if even slightly lower; on theother hand, the 35% mixture is less resistant than the 30% one.

hardness test

The BRINELL hardness method is employed (measurement of the mark left bythe penetration of a steel ball). The test is performed on a durometerISSER STEDT, model Dia testor 2 RC, CONTROLAB company, 93400 STOUEN-FRANCE.

The measurements are carried out with two different standard pressures(15.625 and 31.25 Kp). The dispersions are very low.

The results are given in the table below:

    ______________________________________    Load %       0        10     20     30   35    Brinell hardness                 26.4     20.3   25.8   30.9 33.3    Standard deviation                 0.24     0.54   1.1    0.79 0.44    ______________________________________

It should be noted that the heavier the load, the more resistant thematerial becomes, with the exception of the 10% mixture which provessofter that pure PEEK.

These various results show that the 20% mixture seems a good mechanicalcompromise; it exhibits characteristics close to those of pure PEEK aswell as reasonable resilience. It is hard and ductile at the same time.

b) test of chemical analysis

FIG. 6 shows the diffraction spectrum X of mixture number 5, i.e.comprising of PEEK (80%), tricalcium phosphate (10%) and titaniumdioxide (10%).

The presence of peaks put in evidence by the arrows indicates thepresence of calcium hydroxyapatite in the moulded material.

c) experimental validation

The moulded material obtained according to the example above has beenmachined in order to execute a dental implant with end drill bit andthread, designed to be screwed into the jaw. This implant has beeninstalled with a knurled screwdriver. Using a lever arm fitted withgauges, the tightening torque has been raised to 1.2 Nm (whereas themaximum tightening torque exerted by a practicioner on the screwdriveris estimated at 0.6 Nm).

After removal, the observation of these implants shows that the edges ofthe end drill bit do not exhibit any breakage nor blatant wear.Moreover, no angular deformations due to the screwing action could benoticed.

On the other hand, after analysis, it appears that the human tissues andcells have accepted the implant extremely well from a biologicalviewpoint.

I claim:
 1. A process for obtaining a moulded material, comprised of abiocompatible thermoplastic polymer with hydroxyapatite, for medical orveterinary uses, which comprises:homogeneously mixing the biocompatiblethermoplastic polymer at least with tricalcium phosphate (Ca₃ (PO₄)₂) toobtain a mixture; and subjecting the mixture to an injection orextrusion moulding operation under conditions suited to ensuretransformation of the tricalcium phosphate into calcium hydroxyapatiteand into orthophosphoric acid.
 2. A process according to claim 1,wherein the thermoplastic polymer is mixed at a ratio of 65 to 90% byweight, with 10 to 35% by weight of additional components.
 3. A processaccording to claim 1, wherein the thermoplastic polymer used consists ofpolyether etherketone (PEEK).
 4. A process according to claim 1, furthercomprising incorporating to the mixture, before moulding, at least onebiocompatible metallic oxide selected from the group consisting oftitanium dioxide, zirconium dioxide and aluminum oxide.
 5. A processaccording to claim 4, wherein the metallic oxide used is titaniumdioxide (TiO₂).
 6. A process according to claim 1, wherein the mixturecomprises:polyether etherketone (PEEK); tricalcium phosphate (Ca₃(PO₄)₂); and titanium dioxide (TiO₂).
 7. A process according to claim 6,wherein the mixture comprises:80% by weight of polyether etherketone;10% by weight of tricalcium phosphate; and 10% by weight of titaniumdioxide.
 8. A material for biological or medical uses obtained by theprocess according to claim
 1. 9. A material according to claim 8,comprising:65 to 90% by weight of thermoplastic polymer; 10 to 35% byweight of additional components, in the form of calcium hydroxyapatiteassociated with tricalcium phosphate and with orthophosphoric acid.